Mitinori Saitou, M.D., Ph.D.Professor
The human body consists of a variety of cell types with distinct characters. An essential information code that defines a cell’s unique character is the epigenome, which refers to the whole-genome assembly of epigenetic modifications of chromatin. We are studying the mechanism of germ cell development, which, among all the cell types in the body, shows one of the most dynamic regulations of the epigenome to acquire totipotency, thereby aiming to understand the regulatory basis for many distinct cellular characters and to control them appropriately in vitro.
Research and EducationThe germ cell lineage ensures the creation of new individuals, perpetuating/diversifying the genetic and epigenetic information across the generations. We have been investigating the mechanism for germ cell development, and have shown that mouse embryonic stem cells (mESCs)/induced pluripotent stem cells (miPSCs) are induced into primordial germ cell-like cells (mPGCLCs) with a robust capacity both for spermatogenesis and oogenesis, and for contributing to healthy offspring. We have also shown that human induced pluripotent stem cells (hiPSCs) robustly generate human primordial germ cell-like cells (hPGCLCs). Furthermore, by investigating the development of a non-human primate model, cynomolgus monkeys, we have defined a developmental coordinate of pluripotency among mice, monkeys, and humans, and shown that the germ cell lineage in primates is specified in the nascent amnion, providing a pivotal insight into the biological relevance of the hPGCLC induction pathway. More recently, we have succeeded in differentiating hPGCLCs into human oogonia that undergo a proper epigenetic reprogramming and acquire an immediately precursory state for meiotic entry. We hope that these lines of research will lead to a better understanding of the mechanism for the transmission/diversification of genetic information, for the regulation of epigenetic information, and for the acquisition of totipotency, among mice, monkeys, and humans.
Figure 1. A model for the signaling and transcription architectures for mouse (top) and human (bottom) germ cell specification (Kojima et al., Cell Stem Cell, 2017).
Figure 2. Ultrastructure of hPGCLC-derived oogonium in xenogeneic reconstitute ovaries (xrOvaries) (Yamashiro et al., Science, 2018). The cell bears a clear cytoplasm with sparsely distributed mitochondria with villiform cristae and an ovoid nucleus with loosely packed chromatin and a prominent granular nucleolus. These properties are highly similar to those of human oogonia/gonocytes. Bar, 2 m.
Recent Publications1.Kojima, Y., Yamashiro, C., Murase, Y., Yabuta, Y., Okamoto, I., Iwatani, C., Tsuchiya, H., Nakaya, M., Tsukiyama, T., Nakamura, T., Yamamoto, T., and Saitou, M. GATA transcription factors, SOX17 and TFAP2C drive the human germ-cell specification program, Life Science Alliance, 4, e202000974, 2021.
2.Ohta, H., Yabuta, Y., Kurimoto, K., Nakamura, T., Murase, Y., Yamamoto, T., and Saitou, M. Cyclosporin A and FGF signaling support the proliferation/survival of mouse primordial germ cell-like cells in vitro, Biology of Reproduction, 104, 344-360, 2021.
3.Murase, Y., Yabuta, Y., Ohta, H., Yamashiro, C., Nakamura, T., Yamamoto, T., and Saitou, M. Long-term expansion with germline potential of human primordial germ cell-like cells in vitro, The EMBO Journal, 39, e104929, 2020.
4.Nagaoka, S. I., Nakaki, F., Miyauchi, H., Nosaka, Y., Ohta, H., Yabuta, Y., Kurimoto, K., Hayashi, K., Nakamura, T., Yamamoto T., and Saitou, M. (2020). ZGLP1 is a determinant for the oogenic fate in mice, Science, 367, eaaw4115, 2020.
5.Yamashiro, C., Sasaki, K., Yabuta, Y., Kojima, Y., Nakamura, T., Okamoto, I., Yokobayashi, S., Murase, Y., Ishikura, Y., Shirane, K., Sasaki, H., Yamamoto, T., and Saitou, M. Generation of human oogonia from induced pluripotent stem cells in vitro, Science, 362, 356-360, 2018.
Anatomy and Cell BiologyProfessor: Mitinori Saitou
Assistant Professor: Hiroshi Ohta
Program Specific Assistant Professor: Tomonori Nakamura
Program-Specific Senior Lecturer: Ikuhiro Okamoto
Program-Specific Senior Lecturer (CiRA): Shihori Yokobayashi
Associate Professor: Masahiro Nagano
Associate Professor: Ken Mizuta
Program-Specific Assistant Professor (CiRA): Yoji Kojima
Program Specific Associate Professor: Yukihiro Yabuta